1. Field of the Invention
The present invention relates to radiation-protecting agents which protect the active ingredient of radiopharmaceuticals against radiolysis.
2. Related Art Statement
Radiopharmaceuticals are drugs to be administered into a living body for the purpose of nuclear medicine diagnosis or radiotherapy. In general, radiopharmaceuticals comprise a radioisotope ion itself or an organic compound stably bound with a radioisotope as an active ingredient, and further contain pharmaceutically necessary additives, and many of the radiopharmaceuticals are formulated as aqueous solution. When an organic compound is used as an active ingredient, the radioisotope is incorporated into the molecular structure of active ingredient through covalent bond or coordination bond.
In radiopharmaceuticals, the radiation emitted from radioisotope decomposes the active ingredient by direct action or indirect action of radiation. The term "direct action" means decomposition caused by the direct collision of the radiation itself emitted from radioisotope against active ingredient molecule, while the term "indirect action" means decomposition of active ingredient molecule caused by the attack of water radicals such as OH radical, H radical and hydrated electron which are formed when the energy of the radiation emitted from radioisotope is absorbed by water molecule constituting the solvent. These actions of radiation are called radiolysis, and the radiolysis of an active ingredient is almost exclusively caused by the indirect action, in case of aqueous radiopharmaceuticals in which the concentration of active ingredient is generally low. The number of radicals generated per 100 eV of absorbed radiation energy is called radical yield, which is 2.5 for OH radical, 0.5 for H radical, and 2.7 for hydrated electron. These values and the characteristic feature of the radical reaction suggest that the predominant water radical participating in radiolysis is OH radical in most cases.
Further, water radicals form hydrogen peroxide in the process of the recombination reaction thereof. The hydrogen peroxide thus formed disturbs the active ingredient-forming reaction (complex formation) when technetium-99m (hereinafter abbreviated to Tc-99m), a typical radionuclide for radiopharmaceuticals, is linked to active ingredient through coordination bond. In addition, the hydrogen peroxide accelerates elimination of Tc-99m from active ingredient. In radiopharmaceuticals containing Tc-99m, a reductant (usually, a stannous salt) is added for the purpose of reducing pertechnetate (hereinafter abbreviated to .sup.99m TcO.sub.4.sup.-) and forming a complex with a chelating agent. Hydrogen peroxide oxidizes this reductant to disturb the complex-formation or re-oxidizes the coordinated Tc-99m to accelerate the elimination of Tc-99m. Since the above-mentioned attack of water radicals and the oxidative action of hydrogen peroxide cause decomposition of active ingredient and thereby markedly deteriorate the quality of radiopharmaceuticals, it has hitherto been conventional to add a stabilizer to radiopharmaceuticals in order to prevent the deterioration of drug quality.
In Japanese Patent Publication JP-B-82036894, JP-B-82006409 and JP-B-90033019, there is disclosed a technique of adding ascorbic acid or erythorbic acid as a stabilizer for radiopharmaceuticals labeled with Tc-99m, one of the representative radionuclide used in radiopharmaceuticals.
Ascorbic acid and erythorbic acid proposed as stabilizer in these patent gazettes have a general characteristic feature that they are both reductive substances, and their amount to be added is prescribed based on the amount of stannous salt which is a reductant for Tc-99m. The nature of their stabilizing action lies in decomposing hydrogen peroxide due to the reductivity of these stabilizers and thereby preventing the oxidation of the stannous salt used as reductant. However, these stabilizers, namely ascorbic acid and erythorbic acid, are unusable at all when a readily reducible active ingredient or additive is present in the drug formulation because these stabilizers reductively decompose such active ingredient or additive. For example, in a radiopharmaceutical comprising an active ingredient having porphyrin rings as fundamental chemical structure, the active ingredient is decomposed through a reaction with ascorbic acid as mentioned below, and thereby loses the original pharmaceutical activity.